The incidence and mortality of cancer are on the rise, globally. Targeted therapy has gained significant attention due to tumor complexity and heterogeneity. Therefore, the identification of potential cancer therapeutic targets is critical. Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of the rapamycin (mTOR) signaling pathway is one of the significant cellular signaling pathways that play a valuable role in fundamental intracellular functions. Key players of this pathway have been deeply studied and found to be dysregulated in human cancers. Efforts have been made enormously to target this pathway, many of which are undergoing clinical trials. It is thus important to understand the link between this pathway and tumorigenesis to help make clinical decisions. It is also important to include more potent components with reduced toxicity and greater specificity. It is noteworthy that potential biomarkers that are important to predict response to therapy must be established and clinically approved. This chapter provides a summary of the recent advances and trends in using molecules as inhibitors in human cancer against the PI3K/Akt/mTOR pathway.